Pharmacokinetics and Oral Bioavailability of a Novel PPAR-Sparing Insulin Sensitizer and Its Pharmacologically Active Hydroxy Metabolite in Monkeys and Humans

MSDC0602 (5-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione]) is being developed for the treatment of Type 2 diabetes. It is an insulin sensitizer that is related to the thiazolidinedione pioglitazone (ACTOS™) except MSDC0602 has significantly reduced ability to activate the nuclear transcription factor PPAR. These compounds exert their pharmacology by selectively modulating mitochondrial metabolism resulting, among other things, in improved insulin sensitivity and an increase in brown adipose tissue.   The PPAR-sparing nature of this compound and its pharmacologically active hydroxy metabolite (MSDC-0597) may provide increased therapeutic ratio in clinical practice by avoiding PPAR?-related side effects including fluid retention and weight gain. The intravenous and oral dose pharmacokinetics of MSDC-0602 and MSDC-0597 and the bioavailability of orally administered MSDC-0602 were evaluated in the cynomolgus monkey in preclinical studies and the oral dose pharmacokinetics of both compounds were evaluated in healthy humans as part of a Phase I single and multiple dose tolerance and safety study. Validated non-chiral reversed-phase LC-MS/MS analytical methodology that utilized negative electrospray ionization was used for analysis of monkey and human sodium heparin plasma samples. The analytical ranges for MSDC-0602 and MSDC-0597 were 0.300 to 300 ng/mL and 10.0 to 10,000 ng/mL, respectively, in both monkey and human plasma. Intravenous doses of MSDC-0602 and MSDC-0597 had systemic clearances of 140 and 0.531 mL/min/kg, respectively, in the monkey and confirmed that MSDC-0602 was acting as a prodrug for the delivery of MSDC-0597. Low but significant concentrations of MSDC-0602 were observed in plasma after intravenous administration of MSDC-0597, confirming that the alcohol was converted to the ketone parent in vivo. Assuming quantitative conversion of MSDC-0602 to MSDC-0597, the MSDC-0597 clearance was slightly lower (0.444 ± 0.047 mL/min/kg) after intravenous administration of MSDC-0602 than after intravenous administration of MSDC-0597. The steady state volumes of distribution of MSDC-0602 and MSDC-0597 in monkeys were 27.2 and 0.480 L/kg, respectively. In monkeys, the absolute oral bioavailabilities of MSDC-0597, when administered as unformulated MSDC-0602, were 12% for the non-micronized free acid, 61.6% for the micronized free acid, 67.7% for the non-micronized sodium salt and 83.3% for the non-micronized potassium salt. Single and multiple oral doses of unformulated non-micronized and micronized MSDC-0602 were administered to healthy human subjects at doses ranging from 30 to 1620 mg in the tolerance and safety study. As in the monkey, MSDC-0602 was rapidly metabolized to MSDC-0597 in humans, with the ratio of MSDC-0602 and MSDC-0597 concentrations remaining essentially constant over the entire concentration-time profile. The occurrence of secondary maxima in concentration-time profiles, some of which occurred as long as 24-48 hr post-dose in humans, suggested that enterohepatic recycling occurred. Administration of unformulated micronized vs non-micronized MSDC-0602 resulted in 5.1- and 5.5-fold increases in oral bioavailability in monkey and man, respectively. These data confirmed that the monkey was a suitable animal model for assessing oral bioavailability of MSDC-0602 in humans. Solid dosage forms were selected for further evaluation in humans based on preliminary monkey bioavailability studies.